Drugs of Abuse and Addiction

General Concepts & Neurobiology - Addiction's Core

• Addiction: Compulsive drug use despite harm; chronic relapsing disorder.
• Reward Pathway (Mesolimbic):
  • VTA → NAc; Dopamine (DA) is key for reward.
  • Involves Prefrontal Cortex (PFC), amygdala, hippocampus.
• Neuroadaptation:
  • Tolerance: ↓ drug effect, ↑ dose needed.
  • Dependence: Physiological state; withdrawal on stopping.
  • Withdrawal: Symptoms opposite to drug.
  • Sensitization: ↑ drug effect (e.g., stimulants).
• Key Terms:
  • Reinforcement: Drug promotes self-use.
  • Craving: Intense urge.

⭐ All addictive drugs increase dopamine in the Nucleus Accumbens (NAc) via the mesolimbic pathway.

Opioids - Perilous Pleasure

• Examples: Morphine, heroin, fentanyl, codeine.
• Mechanism: µ, κ, δ receptor agonists in CNS. Presynaptic: ↓$Ca^{2+}$ influx. Postsynaptic: ↑$K^{+}$ efflux. Overall: ↓neurotransmitter release.
• Intoxication: Triad:
  • Miosis (pinpoint pupils)
  • Respiratory depression (life-threatening)
  • Coma
  • 📌 CPR: Coma, Pinpoint pupils, Respiratory depression.
• Withdrawal: Severe flu-like: N/V/D, myalgia, lacrimation, rhinorrhea, piloerection, mydriasis, yawning.
• Management:
  • Overdose: Naloxone (opioid antagonist), 0.4-2mg. Titrate to respiratory effort.
  • Maintenance: Methadone (long-acting oral agonist), Buprenorphine (partial µ-agonist), Naltrexone (oral antagonist, prevents relapse).

⭐ Fentanyl is 50-100x more potent than morphine; high overdose risk.

Depressants (Alcohol & Sedatives) - The Slowdown Spiral

• Alcohol:
  • MOA: GABA-A receptor activation (indirectly), NMDA receptor inhibition. Follows zero-order kinetics of elimination.
  • Acute: Disinhibition, euphoria, ataxia, slurred speech, respiratory depression, coma.
  • Chronic: Liver disease (fatty liver, hepatitis, cirrhosis), pancreatitis, cardiomyopathy, Wernicke-Korsakoff syndrome (thiamine/B1 deficiency).
  • Withdrawal: Tremor, anxiety, insomnia, autonomic hyperactivity (tachycardia, HTN), seizures. Delirium Tremens (DTs) after 48-96 hrs (hallucinations, disorientation, agitation).
    • Management: Benzodiazepines (e.g., Chlordiazepoxide, Diazepam, Lorazepam), thiamine.
  • Dependence Rx: Disulfiram (aversive), Naltrexone (reduces craving), Acamprosate (modulates glutamate).
  • Methanol/Ethylene Glycol Poisoning: Antidotes - Fomepizole (preferred) or Ethanol.
• Sedative-Hypnotics:
  • Benzodiazepines (BZDs): (e.g., Diazepam, Lorazepam, Alprazolam)
    • MOA: ↑ Frequency of GABA-A $Cl^{-}$ channel opening. 📌 Ben Frequently opens.
    • Uses: Anxiety, insomnia, seizures, muscle relaxation, alcohol withdrawal.
    • Antidote: Flumazenil. ⚠️ Can precipitate seizures in BZD-dependent patients or in TCA overdose.
  • Barbiturates: (e.g., Phenobarbital, Thiopental)
    • MOA: ↑ Duration of GABA-A $Cl^{-}$ channel opening; direct GABA-mimetic at high doses. 📌 Barb increases Duration.
    • Uses: Seizures (Phenobarbital), induction of anesthesia (Thiopental).
    • High abuse potential, severe respiratory depression, cardiovascular collapse. Potent CYP450 inducer. No specific antidote.

⭐ Flumazenil, a BZD antagonist, can precipitate seizures in patients with BZD dependence or those on TCAs, limiting its use.

Stimulants & Hallucinogens - Highs & Illusions

• Stimulants: ↑CNS activity, euphoria, sympathetic overdrive.

  • Cocaine:
    • Mech: Blocks DA, NE, 5-HT reuptake.
    • Intox: Mydriasis, tachycardia, HTN, formication (📌 "cocaine bugs"), seizures.
    • Withdrawal: "Crash" (depression, fatigue).
  • Amphetamines (Meth, MDMA):
    • Mech: ↑Release & ↓reuptake DA, NE, 5-HT.
    • Intox: Similar to cocaine. MDMA: +hyperthermia, hyponatremia. Meth: neurotoxic, "meth mouth".
    • Withdrawal: Similar.
  • Nicotine:
    • Mech: nAChR agonist.
    • Withdrawal: Irritability, craving.

• Hallucinogens: Altered perception, mood, thought.

  • Cannabis (THC):
    • Mech: CB1/CB2 agonist.
    • Intox: Conjunctival injection, ↑appetite, dry mouth, amotivational syndrome (chronic).
    • Withdrawal: Irritability, anxiety.
  • LSD:
    • Mech: 5-HT2A agonist.
    • Intox: Visual hallucinations, synesthesia, flashbacks. No significant physical withdrawal.
  • PCP & Ketamine:
    • Mech: NMDA antagonists. Dissociative.
    • Intox (PCP): Nystagmus (rotatory/vertical), aggression, psychosis, analgesia.

    ⭐ PCP intoxication: unpredictable violence, analgesia, nystagmus.

    • Intox (Ketamine): Shorter acting PCP-like effects.

High‑Yield Points - ⚡ Biggest Takeaways

• Acute opioid overdose triad: Pinpoint pupils, respiratory depression, coma. Antidote: Naloxone.
• Benzodiazepine overdose: Antidote is Flumazenil.
• Cocaine toxicity: Sympathomimetic crisis. Manage with benzodiazepines; beta-blockers contraindicated.
• Alcohol withdrawal: Treat with benzodiazepines. Delirium tremens is a medical emergency.
• Disulfiram: Inhibits aldehyde dehydrogenase, causing acetaldehyde syndrome with alcohol.
• Smoking cessation: Key drugs include Varenicline and Bupropion.
• Cannabis: Chronic use linked to amotivational syndrome; hyperemesis syndrome also seen.